title: Genetic ablation of phagocytic NADPH oxidase in mice limits TNFα-induced inflammation in the lungs but not other tissues.
abstract: In vitro and limited in vivo evidence suggests that reactive oxygen species derived from NADPH oxidases (NOX-ROS) play an important role in inflammatory responses by enhancing the activity of redox-sensitive cell signaling pathways and transcription factors. Here, we investigated the role of NOX-ROS in TNFα-induced acute inflammatory responses in vivo, using mice deficient in the gp91(phox) (NOX2) or p47(phox) subunits of NADPH oxidase. Age- and body weight-matched C57BL/6J wild-type (WT) and gp91(phox) or p47(phox) knockout mice were injected intraperitoneally with 50 μg TNFα/kg bw or saline vehicle control and sacrificed at various time points up to 24 h. Compared to WT mice, gp91(phox -/-) mice exhibited significantly diminished (P<0.05) TNFα-induced acute inflammatory responses in the lungs but not other tissues, including heart, liver, and kidney, as evidenced by decreased activation of the redox-sensitive transcription factor NF-κB, and decreased gene expression of interleukin (IL)-1β, IL-6, TNFα, E-selectin, and other cellular adhesion molecules. Similar results were observed in p47(phox -/-) mice. Interestingly, decreased lung inflammation in knockout mice was accompanied by increased leukocyte infiltration into the lungs compared to other tissues. Our data suggest that phagocytic NOX-ROS signaling plays a critical role in promoting TNFα-induced, NF-κB-dependent acute inflammatory responses and tissue injury specifically in the lungs, which is effected by preferential leukocyte infiltration.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. weijian.zhang@oregonstate.edu
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Wei
authors.forename: Ying-Tzang
authors.initials: YT
authors.lastname: Tien
authors.forename: Balz
authors.initials: B
authors.lastname: Frei
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D016207:Cytokines; D019040:E-Selectin; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1